Estimation and inference for semi-competing risks based on data from a nested case-control study

In semi-competing risks, the occurrence of some non-terminal event is subject to a terminal event, usually death. While existing methods for semi-competing risks data analysis assume complete information on all relevant covariates, data on at least one covariate are often not readily available in practice. In this setting, for standard univariate time-to-event analyses, researchers may choose from several strategies for sub-sampling patients on whom to collect complete data, including the nested case-control study design. Here, we consider a semi-competing risks analysis through the reuse of data from an existing nested case-control study for which risk sets were formed based on either the non-terminal or the terminal event. Additionally, we introduce the supplemented nested case-control design in which detailed data are collected on additional events of the other type. We propose estimation with respect to a frailty illness-death model through maximum weighted likelihood, specifying the baseline hazard functions either parametrically or semi-parametrically via B-splines. Two standard error estimators are proposed: (i) a computationally simple sandwich estimator and (ii) an estimator based on a perturbation resampling procedure. We derive the asymptotic properties of the proposed methods and evaluate their small-sample properties via simulation. The designs/methods are illustrated with an investigation of risk factors for acute graft-versus-host disease among N = 8838 patients undergoing hematopoietic stem cell transplantation, for which death is a significant competing risk.